There are strong epidemiologic data suggesting a link between vitamin D deficiency during pregnancy and childhood asthma. Furthermore, there are strong experimental animal data showing that vitamin D is one of the local alveolar paracrine factors that spatiotemporally modulates perinatal pulmonary maturation. However, the mechanistic link between vitamin D deficiency during pregnancy and childhood asthma is not known. Our preliminary data show that vitamin D augments perinatal lung maturation such that its deficiency would perturb normal lung structural and functional development in a way that is consistent with the asthma phenotype in the offspring, providing a compelling mechanistic link between vitamin D deficiency and childhood asthma. We hypothesize that vitamin D deficiency during pregnancy and perinatal periods specifically alters homeostatic Parathyroid Hormone-related Protein/Peroxisome Proliferator-Activated Receptor ? (PTHrP/PPAR?) signaling in the developing lung, resulting in an enhanced myogenic phenotype in both proximal and distal airways, and supplementing with sufficient vitamin D during pregnancy blocks the development of asthma in offspring. Using a rat model of vitamin D deficiency and state-of-the-art molecular tools, we will determine the role of vitamin D in promoting 1) alveolar epithelial-mesenchymal interactions mediated by PTHrP/PPAR? signaling that lead to increased surfactant synthesis and alveolar septation;2) proximal airway smooth muscle differentiation;and examine 3) if vitamin D supplementation during pregnancy and lactation will prevent morphological, structural, and functional pulmonary changes associated with vitamin D deficiency, and hence the consequent predisposition to asthma in offspring. The proposed studies, for the first time, critically evaluate the physiologic role of vitamin D in perinatal pulmonary maturation and could provide novel understanding for the biologic rationale and mechanistic basis for vitamin D supplementation to prevent childhood asthma, a major contributor to childhood morbidity and mortality. These studies are essential to determine the optimal dose of vitamin D, or even better, to find vitamin D analogs or metabolites with optimal respiratory effects without any significant side effects. Furthermore, since asthma is both genetic and environmental in origin, these studies can provide the basis to find genetic variants in PTHrP/PPAR? and Wnt signaling pathways that determine vitamin D's effect on childhood asthma. PUBLIC HEALTH RELEVANCE: There are strong epidemiologic data suggesting a link between vitamin D deficiency during pregnancy and childhood asthma. However, the underlying mechanism for this association is not known. The proposed studies for the first time critically evaluate the role of vitamin D in lung maturation and are likely to provide a biologic rationale and mechanistic basis for vitamin D supplementation to prevent childhood asthma, a major contributor to childhood morbidity and mortality.